JP2516408B2 - Tablets containing coated granules - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a tablet obtained by double-coating coated granules with a water-soluble polymer or an acid-soluble polymer, followed by compression molding. The present invention relates to a tablet containing double coated granules, which prevents the coating of the coated granules from being broken when a pharmaceutical composition containing the coated granules is compression molded.

[Conventional technology and its problems]

It is widely practiced to provide granules with an enteric coating, an acid-soluble coating or an insoluble coating to impart various functions such as taste and odor masking and sustained release. The coated granules are provided as they are, or filled in hard gelatin capsules or soft gelatin capsules, but when compressed into tablets, the compression force at that time destroys the coating and loses its function. It often changes and changes. Therefore, when preparing a tablet-type sustained-release preparation, after predicting the destruction of the coating film by compression in advance, by coating with an insoluble polymer or the like, to produce granules with further suppressed release, It is performed by compression molding into tablets. However, the breakdown of the coating film during compression molding depends on the state of the coating film, the properties of the uncoated portion, etc., and its prediction is very difficult.Therefore, the release characteristics of the obtained tablets are different from those predicted in advance. There are many.

[Means for solving the problem]

In such a situation, the present inventor has conducted diligent research on the damage of the coating when the coated granules are compression molded, and as a result,
We have found that a tablet obtained by coating a coated granule with a water-soluble polymer or an acid-soluble polymer and compression-molding it can prevent the coating from breaking without impairing the properties and functions of the coated granule, and completed the present invention.

That is, the present invention provides a tablet obtained by compression molding a pharmaceutical composition containing coated granules coated with a coating comprising one or more of insoluble polymers, enteric polymers or waxes. A tablet comprising coated granules, characterized in that the granules are further coated with a protective coating of 15 to 50% by weight of the coated granules of a water-soluble polymer or an acid-soluble polymer.

The water-soluble polymer or the acid-soluble polymer used in the present invention can withstand the compressive force during compression processing without substantially changing the function of the coating of the coated granule when administered in vivo. Thus, it has a role of protecting the coated granules. Therefore, the protective coating used in the present invention may be any water-soluble polymer or acid-soluble polymer capable of playing the above-mentioned role, and is not particularly limited, but as a preferred specific example, the water-soluble polymer is: Hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol,
Examples of the acid-soluble polymer include gelatin and the like, and examples of the acid-soluble polymer include aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate.
These polymers may be used alone or in admixture of two or more, and when administered into a living body, they do not substantially impair the function of the coating of the coated granules and endure the compressive force during compression processing. If the coated granules can be protected so that they can be obtained, they may be mixed with an enteric or water-insoluble polymer or wax.

In order to produce the tablet of the present invention, first, the coated granules are coated with a water-soluble polymer or an acid-soluble polymer by a conventional method to produce double coated granules. At that time, if necessary, an appropriate plasticizer, lubricant, colorant, etc. can be added. Then, the double-coated granules are mixed with a conventionally known tableting composition containing, if necessary, suitable excipients, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, stabilizers and the like. It is manufactured by mixing with a material and compression molding.

In addition, the coating of the coated granule is a sustained-release or enteric-coated coating, and in order to obtain a certain blood concentration in the early stage after administration, the active pharmaceutical agent can be incorporated into the protective coating or the uncoated granule part.

Furthermore, the tablet of the present invention can be made into a dry-coated tablet, a multilayer tablet, a film-coated tablet, and a sugar-coated tablet by a commonly used method.

[Action and effect]

The thus-obtained tablets containing the coated granules of the present invention, due to the action of the water-soluble polymer or acid-soluble polymer coating, do not impair the function of the coating granules even when subjected to compression molding, and have the desired effect. Is what you can get.

〔Example〕

The present invention will be described in detail below by showing Examples of the present invention.

Example 1 Production of naked granules a: diclofenac sodium 800 g, corn starch 400 g
Are mixed and finely pulverized to obtain a fine powder. Fine powder was tumbled to form spherical granules by pouring granules while rolling a liquid in which 475 g of hydroxypropylcellulose was dissolved in 475 g of ethyl alcohol with 600 g of sucrose sized to 28-35 mesh as the core, and spherical granules were produced.
Dry for an hour. Pass through 16 mesh of this dry granules, 35
Those that do not pass through the mesh are referred to as bare granules a.

Example 2 Production of coated granules b: 800 g of the naked granules a produced in Example 1 is placed in a fluidized bed coating apparatus and spray coated with 2746 g of a coating solution having the following composition according to a conventional method to produce coated granules b. The coating amount of this product was 23% based on the bare granules.

Composition% Methacrylic acid copolymer L 6.5 Talc 0.2 Ethyl alcohol 93.3 Total 100.0 Example 3 Production of double coated granule c: 500 g of coated granule b prepared in Example 2 was put in a fluidized bed coating apparatus and the composition shown below was applied. Spray coating with 1389 g of the coating solution (1) is carried out according to a conventional method to give double coated granules (c). The coating amount of this product is 20 relative to coated granule b.
%Met.

Composition% Hydroxypropyl methylcellulose 6.5 Macrogol 6000 0.5 Talc 0.2 Ethyl alcohol 66.8 Purified water 27.0 Total 100.0 Example 4 Production of tablets of the present invention Crystalline cellulose 240 g, corn starch 25 g, lactose 172.
To the mixed powder of 5 g, 125 g of 50% ethyl alcohol solution of 10% (w / w) hydroxypropyl cellulose was added and kneaded.
Granules were manufactured by a conventional method. Next, 203.6 g of the granules, double coated granules c168.4 g obtained in Example 3, 20 g of carboxymethyl cellulose calcium, 4 g of magnesium stearate, and 4 g of talc were uniformly mixed and compression-molded, and the weight per tablet was 400 mg, A tablet of the present invention having a diameter of 10 mm was produced.

Example 5 Preparation of comparative tablets: 240 g crystalline cellulose, 25 g corn starch, lactose 172.
To the mixed powder of 5 g, 125 g of 50% ethyl alcohol solution of 10% (w / w) hydroxypropyl cellulose was added and kneaded.
Granules were manufactured by a conventional method. Then, 203.6 g of the granules, 140.3 g of the coated granules b of Example 2, 28.1 g of lactose, 20 g of calcium carboxymethyl cellulose, 4 g of magnesium stearate, and 4 g of talc were uniformly mixed and then compression molded, and 1
Tablets having a weight of 400 mg and a diameter of 10 mm were produced.

Example 6 The tablet of the present invention obtained in Example 4, the comparative tablet obtained in Example 5 and the coated granules b were used as the eluent for the test solution of pH 4.5 for 30 minutes from the start of the test. After 60 minutes, a test solution of pH 6.8 (Japanese Pharmacopoeia – 11th revision, 2nd revision)
Liquid), and the rotating paddle method (Japanese Pharmacopoeia-the 11th revision) 10
It was measured at 0 rpm. The results are shown in Table 1. The tablet of the present invention does not show the breakage of the coating like the comparative tablet, and exhibits the same dissolution characteristics as the comparative granule.

Example 7 Production of Naked Granules d: Theophylline 800 g, corn starch 375 g, sucrose 600 g sized to 28 to 35 mesh and hydroxypropyl cellulose 25 g were dissolved in ethyl alcohol 475 g.
Bare granules d were obtained in the same manner as in Example 1.

Example 8 Production of coated granules e: 800 g of the naked granules d produced in Example 7 is placed in a fluidized bed coating apparatus and spray-coated with 1684 g of a coating solution having the following composition according to a conventional method to produce coated granules e. The coating amount of this product was 8% based on the naked granules.

Composition% Ethyl cellulose 2.7 Polyvinylpyrrolidone K30 0.9 Talc 0.2 Ethyl alcohol 96.2 Total 100.0 Example 9 Production of double coated granules f used in the present invention: 600 g of coated granules e produced in Example 8 was put in a fluidized bed coating apparatus. A double coating granule f is prepared by spray coating with 2000 g of a coating solution having the following composition according to a conventional method. The coating amount of this product is
It was 20%.

Composition% Polyvinyl acetal Diethylaminoacetate 6.0 Ethyl alcohol 47.0 Acetone 47.0 Total 100.0 Example 10 Production of tablets of the present invention: Double coated granules f 147.8 g, crystalline cellulose 150 g, lactose
46.2 g, 3 g of magnesium stearate and 3 g of talc were uniformly mixed and then compression-molded to give a tablet of the present invention having a weight of 350 mg and a diameter of 9 mm.

Example 11 Production of comparative tablet: Coated granule e123.2g, crystalline cellulose 150g, lactose 70.8g,
3 g of magnesium stearate and 3 g of talc were uniformly mixed and compression-molded to give tablets each weighing 350 mg and having a diameter of 9 mm.

Example 12 The tablet of the present invention obtained in Example 10, the comparative tablet obtained in Example 11, the elution of coated granule e using a liquid of pH 1.2 as the eluent, the rotary paddle method (Japanese Pharmacopoeia-No. 11 amendment), 100
It was measured at rpm. The results are shown in Table 2. The tablet of the present invention shows almost the same dissolution characteristics as the comparative granule, and the release rate is not changed like the comparative tablet.

Example 13 Production of naked granules g To a mixed powder of 1400 g of cephalexin, 160 g of lactose, 200 g of purified sucrose, and 200 g of crystalline cellulose, a solution prepared by dissolving 40 g of hydroxypropyl cellulose in 760 g of ethyl alcohol was added and kneaded. This kneaded product is granulated using a cylindrical granulator, and then spherical granules are produced using a Marumerizer at 55 ° C.
Dry for 2 hours. Of these dry granules, those which pass through 16 mesh and do not pass through 35 mesh are designated as naked granules g.

Example 14 Production of coated granules h: 800 g of the bare granules g produced in Example 13 was placed in a fluidized bed coating apparatus and 3582 g of coating liquid having the composition of Example 2
The coated granules h are produced by spray coating according to a conventional method. The coating amount of this product is 30% with respect to bare granules.
Met.

Example 15 Production of double coated granules i: 400 g of the coated granules h produced in Example 14 are placed in a fluidized bed coating apparatus and a coating solution 1111 of the composition of Example 3 is obtained.
Spray coating with g according to the usual method to produce double coated granules i. The coating amount of this product was 20% with respect to the coated granules h.

Example 16 Production of tablets of the present invention: To a mixed powder of 700 g of cephalexin, 90 g of lactose and 200 g of purified sucrose, a solution of 10 g of hydroxypropylcellulose dissolved in 190 g of ethyl alcohol was added and kneaded, and dried at 55 ° C. for 2 hours, Granules were manufactured by a conventional method. Then this granule 5
3.6 g, double coated granules i of Example 15, i195 g, crystalline cellulose 143.4 g, magnesium stearate 4 g, and talc 4 g were uniformly mixed and then compression-molded, and the weight per tablet was 800 mg.
A tablet of the present invention having a diameter of 13 mm was produced.

Example 17 Production of comparative tablet: To a mixed powder of 700 g of cephalexin, 90 g of lactose, and 200 g of purified sucrose, a solution of 10 g of hydroxypropylcellulose in 190 g of ethyl alcohol was added and kneaded, and dried at 55 ° C. for 2 hours, Granules were produced by the method. Then this granule 5
3.6 g, coated granule h of Example 14 162.5 g, crystalline cellulose 14
3.4 g, lactose 32.5 g, magnesium stearate 4 g, and talc 4 g are uniformly mixed and then compression-molded, and weight per tablet
800 mg tablets with a diameter of 13 mm were produced.

Example 18 Preparation of comparative granules: 10.7 g of bare granules and 32.5 g of coated granules were mixed, and then 432 m
It was packaged in g to prepare granules.

Example 19 The tablet of the present invention obtained in Example 16, the comparative tablet obtained in Example 17, the comparative granules obtained in Example 18 as the eluent, the test starting from 30 minutes until pH 1.2 Test solution of Japanese Pharmacopoeia (11th revision, 1st fluid), pH 6.8 after 30 minutes to 60 minutes (Japanese Pharmacopoeia-11th revision, 2nd fluid)
Using the rotating paddle method (Japanese Pharmacopoeia-11th revision) 100r.
Measured in pm. Table 3 shows the results. The dissolution characteristics of the tablets according to the present invention did not change much compared to the comparative granules, whereas the dissolution characteristics of the comparative tablets changed significantly.

Claims (3)

(57) [Claims] 1. A tablet obtained by compression-molding a pharmaceutical composition containing a coated granule coated with a coating comprising one or more of an insoluble polymer, an enteric polymer and waxes. Is coated with a protective coating of water-soluble polymer or acid-soluble polymer in an amount of 15 to 50% by weight based on the coated granules. 2. The tablet according to claim 1, wherein the active drug is contained in coated granules. 3. The tablet according to claim 1, wherein the coated granule and the uncoated granule part contain an active pharmaceutical agent.